title: Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.
abstract: Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity.
authors.affiliation: Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Sun
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Meerbrey
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kessler
authors.forename: Chunshui
authors.initials: C
authors.lastname: Zhou
authors.forename: Ilenia
authors.initials: I
authors.lastname: Migliaccio
authors.forename: Don X
authors.initials: DX
authors.lastname: Nguyen
authors.forename: Natalya N
authors.initials: NN
authors.lastname: Pavlova
authors.forename: Maria
authors.initials: M
authors.lastname: Botero
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bernardi
authors.forename: Earlene
authors.initials: E
authors.lastname: Schmitt
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.forename: Mamie Z
authors.initials: MZ
authors.lastname: Li
authors.forename: Noah
authors.initials: N
authors.lastname: Dephoure
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Mitchell
authors.initials: M
authors.lastname: Rao
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis; D011499:Protein Processing, Post-Translational; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12